The present invention relates to novel physiologically active substances, herein identified as KS-506a, KS-506x, KS-506g, KS-506m and KS-506h, and a process for the production thereof.
KS-506a, KS-506x and KS-506g have an activity to inhibit cyclic nucleotide phosphodiesterase and are useful as pharmaceuticals such as bronchodilators, cardiotonics, vasodilators, hormone secretomotor agents and antiallergic agents and also as reagents for the research of cyclic adenosine-3',5'-monophosphoric acid (hereinafter referred to as cAMP) and cyclic guanosine-3',5'-monophosphoric acid (hereinafter referred to as cGMP).
KS-506m and KS-506h have an activity to inhibit histamine release and are useful as pharmaceuticals such as antiallergic agents and antiinflammatory agents.
cAMP and cGMP are substances which play an important role as a second messenger in the signal transduction system in a living body. It is generally considered that they are involved in contraction of smooth muscles of bronchus and blood vessel, contraction of cardiac muscle, secretion of hormone, release of transmitters such as histamine, platelet aggregation, cell growth and differentiation, and the like. Cyclic nucleotide phosphodiesterase (hereinafter referred to as PDE) is an enzyme which hydrolyzes cAMP and cGMP to form adenosine-5'-monophosphoric acid and guanosine-5'-monophosphoric acid, respectively. It has been known that substances inhibiting the enzyme raise the concentration of cAMP and cGMP in a living body and as a result exhibit a bronchodilator action, a smooth muscle-relaxing action, a cardiotonic action, a hormone secretomotor action, an action of inhibiting the release of transmitters such as histamine which is one of the causative substances of allergy, an antithrombotic action, etc.
Heretofore, the following substances have been known as substances which are produced by microorganisms and have a PDE-inhibiting action:
(1) Terferol
J. Antibiot. 37, 6-9 (1984) ##STR1##
(2) Griseolic acid
J. Antibiot. 38, 823 (1985) ##STR2##
(3) Reticurol
J. Antibiot. 28, 558-560 (1975) ##STR3##
(4) PDE-I, II
Agr. Biol. Chem. 42, 1331-1336 (1978) ##STR4##
(5) KS-619-1
J. antibiot. 40, 1104-1110 (1987) ##STR5##
(6) K-259-2
J. Antibiot. 40, 1092-1100 (1987) ##STR6##
(7) Genistein
Agr. Biol. Chem. 51, 3003-3009 (1987) ##STR7##
Substances (1) to (5), substance (6) and substance (7) are produced by actinomycetes of the genus Streptomyces, the genus Micromonospora and the.. genus Streptosporangium, respectively. Further, TPI having the following structure has been known as a substance which is produced by a fungus and inhibits PDE: ##STR8##
Furthermore, KS-503c which is produced by a microorganism belonging to the genus Hormonema and has a PDE-inhibiting activity has been disclosed in Japanese Patent Application No. 39225/1988.
As chemically synthesized substances, there have been known theophylline, papaverine and the like used as pharmaceuticals such as cardiotonics and vasodilators.
As compounds which are produced by microorganisms and have an activity to inhibit histamine release, there have been known K-252 (U.S. Pat. 4,555,402) and KT 5556 (Japanese Published Unexamined Patent Application No. 176531/1986) produced by microorganisms belonging to the genus Nocardiopsis.